Inflammation is the coordinated response to tissue injury or infection. Inflammation begins with the release of local release of chemotactic factors, platelet activation, and initiations of the coagulation and complement pathways. These events stimulate the local endothelium, promoting the extravasation of neutrophils and monocytes. The second phase of inflammation is characterized by the influx into the tissue of cells of the adaptive immune system, including lymphocytes. The subsequent resolution phase, when apoptosis of the excess leukocytes and engulfment by tissue macrophages takes place, is also characterized by repair of tissue damage by stromal cells, such as fibroblasts.
In such repair mechanisms local quiescent fibroblasts migrate into the affected area, produce extracellular matrix proteins, and promote wound contraction or fibrosis. It has also been suggested that is that circulating fibroblast precursor cells, fibrocytes, which are present within the blood migrate to the sites of injury or fibrosis, where they differentiate and mediate tissue repair and other fibrotic responses. Fibrocytes differentiate from a CD14+ peripheral blood monocyte precursor population and express markers of both hematopoietic cells (CD45, MHC class II, CD34) and stromal cells (collagen types I and III and fibronectin). Mature fibrocytes rapidly enter sites of tissue injury where they secrete inflammatory cytokines, as well as extracellular matrix proteins, other cytokines and pro-angiogenic molecules, which may result in fibrosis.
Fibrocyte differentiation is associated with a variety of fibrotic diseases including but not limited to scleroderma, keloid scarring, rheumatoid arthritis, lupus, nephrogenic fibrosing dermopathy, and idiopathic pulmonary fibrosis. They play a role in the formation of fibrotic lesions after Schistosoma japonicum infection in mice and are also implicated in fibrosis associated with autoimmune diseases. Fibrocytes have also been implicated in pathogenic fibrosis associated with radiation damage, Lyme disease and pulmonary fibrosis, as well as stromal remodeling in pancreatitis and stromal fibrosis, whereas lack of such fibrocytes is associated with pancreatic tumors and adenocarcinomas. Fibrosis additionally occurs in asthma patients and possibly other pulmonary diseases such as chronic obstructive pulmonary disease when fibrocytes undergo further differentiation into myofibroblasts.
A specific set of diseases that are known to involve unchecked fibrotic response are idiopathic interstitial pneumonias, a diverse group of chronic pulmonary diseases characterized by varying levels of pulmonary fibrosis. The major factors driving the dominant pulmonary fibrotic response associated with various histologically distinct forms of idiopathic interstitial pneumonia (IIP) remains poorly defined, thereby contributing to the lack of effective clinical treatments for these diseases. (Green, Overview of pulmonary fibrosis. Chest 2002; 122 (suppl. 6):334S-9S). Although many of these diseases exhibit a fibroproliferative response in the alveolar microenvironment leading to respiratory impairment, the degree of fibrotic change varies considerably among them. (Nicholason Am. J. Resp. Crit. Car Med/2000:162:2213-7; Chapman J. Clin., Invest., 2004; 113:148-57). Equally perplexing is the clear demonstration that anti-inflammatory agents provide therapeutic benefit in less severe forms of IIP, such as non-specific interstitial pneumonia (NSIP) and respiratory bronchiolitis/interstitial lung disease (RBILD), but they often fail to prevent respiratory failure in patients with the most severe and deadly form of IIP—usual interstitial pneumonia (UIP). (Flaherty et al., Am. J. Med., 110:278-282 (2001); Lynch et al., Curr. Opin. Pulm. Med., 7:298-308 (2001); Flaherty et al., Thorax, 58:143-148 (2003))
The existence of distinct foci of fibroblasts, or fibroblastic foci, is an important pathological feature associated with a poor prognosis and a fatal outcome in idiopathic interstitial pneumonia. (King et al., Am. J. Respir. Crit. Care Med., 164:1025-1032 (2001)) Newer treatments may follow after the elucidation of the shared and divergent events that contribute to pulmonary fibrotic changes during the initiation and maintenance of IIP. (van den Blink et al., Arch. Immunol. Ther. Exp. (Warsz), 48:539-545 (2000)) CC chemokine receptor 7 (CCR7; which binds MIP-3b/CCL19 and 6-Ckine/CCL21 (Nagira et al., J. Biol. Chem., 272:19518-19524 (1997)) and CX chemokine receptor 4 (CXCR4; which binds SDF-1/CXCL12 (Forster et al., J. Immunol., 160:1522-1531 (1998)) are chemokine receptors that were widely recognised as being limited in their expression to cells of haemopoietic origin. (Kim et al., J. Leukoc. Biol., 66:455-461 (1999); Kim et al., J. Clin. Invest., 108:1331-1339 (2001)) During immune responses, CCR7 expression facilitates the movement of mature dendritic cells (Sallusto et al., Eur. J. Immunol., 29:1617-1625 (1999)) to lymphoid tissues, regulates the localisation of T helper type 1 and 2 cells within the spleen, (Randolph et al., Science, 286:2159-2162 (1999)) and directs T helper type 2 cells to the allergic lung. (Hammad et al., J. Immunol., 169:1524-1534 (2002)) CXCR4 expression and effects were largely limited to bone marrow derived immune cells. (Ward et al., Biochem. J., 333:457-470 (1998); Gonzalo et al., J. Immunol., 165:499-508 (2000)) Recent evidence showing that the expression of CCR7 and CXCR4 by breast tumour cells allows these cells to metastasize to the lung has modified this immunocentric paradigm. (Muller et al., Nature, 410:5-056 (2001)) Breast cells do not express these chemokine receptors or respond to the ligands that bind them. (Muller et al., Nature, 410:50-56 (2001)) This observation has been extended to several metastasizing tumour types, including melanoma (Murakami et al., J. Dermatol. Sci., 36:71-78 (2004)) and various forms of leukaemia. (Tavor et al., Cancer Res., 64:2817-2824 (2004); Ghobrial et al., Mayo Clin. Proc., 79:318-325 (2004))
Chronic pulmonary fibrosis results from scarring throughout the lungs which can be caused by many conditions including chronic inflammatory processes (sarcoidosis, Wegener's granulomatosis), infections, environmental agents (asbestos, silica, exposure to certain gases), exposure to ionizing radiation (such as radiation therapy to treat tumors of the chest), chronic conditions (lupus, rheumatoid arthritis), and even certain medications. In a condition known as hypersensitivity pneumonitis, fibrosis of the lung can develop following a heightened immune reaction to inhaled organic dusts or occupational chemicals. This condition most often results from inhaling dust contaminated with bacterial, fungal, or animal products. In some types of pulmonary fibrosis, such as nonspecific interstitial pneumonitis (NSIP), the subject may respond to immune suppressive therapy. Where, as often happens, chronic pulmonary inflammation and fibrosis develop without an identifiable cause, the subject suffering from the disease often will not respond to medical therapy. This is particularly true of subjects suffering from idiopathic pulmonary fibrosis (IPF). The treatment options for idiopathic pulmonary fibrosis are very limited. There is no evidence that any medications can help this condition, since scarring is permanent once it has developed. Lung transplantation is the only therapeutic option available. Research trials using different drugs that may reduce fibrous scarring are ongoing. Since some types of lung fibrosis can respond to corticosteroids (such as Prednisone) and/or other medications that suppress the body's immune system, these types of drugs are sometimes prescribed in an attempt to decrease the processes that lead to fibrosis. Nevertheless, it is well-recognized that at present there are no treatments for fibrosing diseases. It is standard clinical practice to give patients prednisone and azathioprine but there is no data showing that these drugs provide any therapeutic benefit. In fact, the side-effects of these drugs may contribute to mortality in UIP patients.
While chemokines may be involved with the formation of fibroblastic foci and the amplification of the fibrotic response in pulmonary fibrosis, the particular role of the profibrotic mediator milieu present during chronic pulmonary fibrosis remains unclear. The present invention identifies the role of specific chemokines and their receptors and provides for new methods and compositions for therapy, especially for the idiopathic disorders that are refractory to medical therapy.